Regulatory affairs: Corticosteroids and the skin

Abstract

Cholesterol-like structures have been found in Precambrian shales some 2.7 billion years old. Clearly, this class of compounds was essential to the most primitive forms of life. The steroids are homologues of cholesterol and all have the same steroidal skeleton but differ particularly in substituents linked to the 17-carbon atom or in the direction these project into space. It was Chevreul, in 1812, who named the ‘nonsaponifiable fat’ he isolated from gallstones as ‘cholesterol’. A hundred years passed before Windaus drew attention to the biological importance of the steroids, but it was not until 1932, and after he had been awarded a Nobel prize for discovering vitamin D, that he described the formula of cholesterol. Although the adrenal glands had been discovered during the Renaissance period, it was not until 1849 that Addison realized the connection between these organs and the disease that carries his name. Then in 1932 it became clear to both Thorn, who demonstrated the effect of ‘cortin’ on adrenalectomized cats, and Cushing, who in the same year described the syndrome that bears his name, that the adrenal glands produce a biologically very active compound. Working for the Mayo Foundation in cooperation with Parke Davis, Kendall processed 150 tons of adrenal glands between 1935 and 1949. Parallel work was being undertaken by Organon in The Netherlands, in conjunction with Reichstein in Switzerland. Kendall, working in the post-war period at US Merck, sold his entire supply of adrenal extract to a friend, Hench, who believed that rheumatoid arthritis was due to adrenal insufficiency. The dramatic effects of cortisone on a patient treated by Hench led Merck to set up production of cortisone from bile. In 1950, Kendall, Hench and Reichstein were awarded a Nobel prize for their discovery of the hormones of the adrenal cortex, their structure and biological effects. Other players in the steroid field include Ruzicka, who was awarded the Nobel prize in 1939, and Russel Maker who, on breaking with Parke Davis, set up ‘Laboratorios Hormonas’ in Mexico in the 1940s to produce progesterone from plant materials. This later led to the foundation of Syntex. Supply of raw materials was a problem. Upjohn managed to produce 50 g of cortisone from the adrenal glands of 2 million pigs! The effects of cortisone applied to the skin were disappointing. Sulzberger and Witten first demonstrated the value of topically applied hydrocortisone in 1952. In 1961, Folker’s discovery of mevalonic acid made possible synthetic routes of production and in 1964 Bloch in the